Aliphatic nitriles are commercially important, but toxic, organic chemicals. Each day, thousands of American workers are potentially at risk from nitrile poisoning. The acute toxicity of these nitriles has been attributed to the slow metabolic release of cyanide. In the case of succinonitrile, the reaction appears to be mediated via a two-step pathway firstly through hepatic oxidases and then by alcohol dehydrogenase. I propose to test other nitriles by: Specific Aim 1: establishing the effectiveness of alcohol dehydrogenase inhibitors to antagonize the acute toxicity of nitriles in mice; Specific Aim 2: testing multiple doses of alcohol dehydrogenase inhibitors with or without coadministration of thiosulfate as antidotal regimens in mice; Specific Aim 3: determining the ability of oxidized nitriles to serve as substrates for alcohol dehydrogenase in vitro; and Specific Aim 4: testing the ability of unusual microsomal enzyme inducers to potentiate the acute toxicity of nitriles in mice. My objective is to develop a better understanding of nitrile bioactivation and detoxification, and to suggest safer and effective antidotes for the management of human intoxication.